This proposal is part of an Interactive Research Project Grant (IRPG) which is being submitted with Dr. Raymond F. Schinazi. Specifically, his laboratory will evaluate all compounds that are prepared under this application. As leads develop, these investigators will work collaboratively to optimize the antiviral profile of the compounds. The project will focus on the continued development of practical methodology for the synthesis of purine and pyrimidine nucleoside analogues. Specifically, these studies include the development of methodology for intramolecular 3'- and 5'-transfer glycosylations, the selective fluorination of nucleoside analogues, the diastereoselective transglycosylation of lactol derivatives with nucleoside base surrogates, the diastereoselective additions of purine and pyrimidine bases to glycals, and combinatorial synthesis of nucleoside analogue libraries. The project will also include the continued synthesis and evaluation of selected D- and L-nucleoside analogue targets which possess favorable anti-HIV/HBV profiles. These include dideoxy purine and pyrimidine nucleoside analogues with an emphasis on fluorinated derivatives, heteranucleosides; 6-substituted pyrimidine nucleoside analogues; phosphorylated nucleoside analogues, including phospholipid conjugates which target selected organs of tissues.